Multiple myeloma (MM) is the second most common hematologic malignancies and is currently considered incurable with a 5-7 year median survival. Newer drugs, such as the proteasome inhibitors, immunomodulatory drugs and monoclonal antibodies in combination with more traditional drugs enable better clinical responses. However, development of resistance to these drugs is still the major cause of patient demise. There is also a significant fraction of newly diagnosed MM patients who are refractory even to these newer drugs and thus have not benefited from the recent therapeutic advancements. We previously found that many MM patient-derived bone marrow mesenchymal stromal cells (BMSCs), a key MM tumor microenvironment cell type, secrete factor(s) capable of activating transcription factor NF-?B and causing proteasome inhibitor resistance in MM cells. We now identified HAPLN1 (hyaluronan and proteoglycan link protein 1) as a responsible BMSC secreted factor that also causes such drug resistance in MM cells in vitro and in vivo. RNA-seq and bioinformatic analyses revealed that HAPLN1 induces large-scale transcriptomic changes, including induction of a host of antiapoptotic genes. Accordingly, HAPLN1 also causes resistance to multiple other drugs in MM cells in vitro. HAPLN1 expression is higher in MM BMSCs relative to normal BMSCs, and proteolytic forms of HAPLN1 are often detected in bone marrow plasma from highly therapy refractory MM patients. Thus, we hypothesize that HAPLN1 is a new oncogenic factor and multi-drug resistance inducer in MM disease. This hypothesis will be tested by determining the pathologic role of HAPLN1 in primary MM patient cells and in vivo (Aim 1), elucidating the mechanism of HAPLN1-mediated drug resistance in MM (Aim 2), and immuno-targeting HAPLN1-mediated drug resistance in MM (Aim 3). Overall, the proposed study may identify soluble HAPLN1 as a novel marker for therapy resistance in MM, as well as a new therapeutic target to prevent or reduce the multi-drug resistance problem in MM.